Although 35% of smokers attempt to quit each year, only 3 - 5% abstain for a year (ACS, 2001). Low success rates can be attributed to the strong addictive properties of nicotine and to associated withdrawal symptoms; avoidance of the symptoms of nicotine withdrawal contributes to nicotine addiction and may facilitate relapse (Kenny & Markou, 2001). One affective symptom of nicotine withdrawal is impaired cognitive function (e.g. Kleinman et al., 1973). For example, hippocampus-dependent learning is disrupted during nicotine withdrawal (Davis et al., 2005). The proposed studies will identify neural and molecular substrates of nicotine withdrawal-associated deficits in learning. Specific Aim 1 will use direct drug infusion to define the role of the hippocampus in nicotine withdrawal-associated deficits in learning. Specific Aims Two and Three will examine nicotine withdrawal-associated changes in learning-related activation of ERK 1 and ERK 2, and CREB, second messengers and a transcription factor involved in learning and addiction (Abel & Lattal, 2001; Nestler, 2002). Identifying the neural and cellular mechanisms that underlie nicotine withdrawal-associated deficits in learning will aid in the development of effective therapeutics. [unreadable] [unreadable] [unreadable]